1. Field of the Invention
The present invention is related to parenteral solutions containing 7-Halo-1,2,3,4-tetrahydro-3-aryl-6-quinazoline sulfonamides.
2. Description of the Related Art
Metolazone is a quinazoline diuretic approved for use in an oral tablet form (MYKROX) for the treatment of hypertension alone or in combination with other anti-hypertensive drugs of a different class. This compound acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule in the kidney. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal-tubular exchange site results in increased potassium excretion.
To treat hypertension, the compound may be administered in oral dosage forms such as in the form of a tablet containing from 0.5-10 mg of metolazone, or it may be administered in the form of an intravenous solution. Metolazone is also indicated for use in treating heart failure and renal disease. Further, when metolazone is combined with furosemide (lasix), the effectiveness of the diuretics is greatly enhanced. Furosemide can be administered intravenously to obtain the best and most rapid diuretic effect in emergencies. However, there is no intravenous formulation available of metolazone (at pH range of 6.8-8 and concentration ranging from 5 to 15 ml/mg) since metolazone is sparingly soluble in most solvents. Metolazone is only sparingly soluble in water, but is said to be somewhat more soluble in plasma, blood, alkali and organic solvents.
U.S. Pat. Nos. 3,360,518 and 3,557,111 disclose methods for preparing metolazone.
And previously, from this laboratory, we have disclosed methods for solubilizing metolazone in U.S. Pat. Nos. 5,633,240, 5,684,009 and 5,814,623.
Previous formulations used buffered alkaline solutions with a pH>9. The basic conditions used may cause degradation of metolazone, the active ingredient. Also it is not desirable to admix highly alkaline solutions with the body fluids (in vivo) as the resulting situation may cause deleterious effects such as irritation at the sight of injection or thrombosis.